Search

Abstract: In healthy subjects, brain activation in motor regions is greater during the visual perception of “natural” target motion, which complies with the two‐thirds power law, than of “unnatural” motion, which does not. It is unknown whether motion perception is normally mediated by a specific network that can be altered in the setting of disease. We used block‐design functional magnetic resonance imaging and covariance analysis to identify normal network topographies activated in response to “natural” versus “unnatural” motion. A visual motion perception‐related pattern (VPRP) was identified in 12 healthy subjects, characterized by covarying activation responses in the inferior parietal lobule, frontal operculum, lateral occipitotemporal cortex, amygdala, and cerebellum (Crus I). Selective VPRP activation during “natural” motion was confirmed in 12 testing scans from healthy subjects. Consistent network activation was not seen, however, in 29 patients with dystonia, a neurodevelopmental disorder in which motion perception pathways may be involved. Using diffusion tractography, we evaluated the integrity of anatomical connections between the major VPRP nodes. Indeed, fiber counts in these pathways were substantially reduced in the dystonia subjects. In aggregate, the findings associate normal motion perception with a discrete brain network which can be disrupted under pathological conditions. [ABSTRACT FROM AUTHOR]

Introduction: Pre-clinical markers of Parkinson’s Disease (PD) are needed, and to be relevant in pre-clinical disease, they should be quantifiably abnormal in early disease as well. Handwriting is impaired early in PD and can be evaluated using computerized analysis of drawn spirals, capturing kinematic, dynamic, and spatial abnormalities and calculating indices that quantify motor performance and disability. Digitized spiral drawing correlates with motor scores and may be more sensitive in detecting early changes than subjective ratings. However, whether changes in spiral drawing are abnormal compared with controls and whether changes are detected in early PD are unknown. Methods: 138 PD subjects (50 with early PD) and 150 controls drew spirals on a digitizing tablet, generating x, y, z (pressure) data-coordinates and time. Derived indices corresponded to overall spiral execution (severity), shape and kinematic irregularity (second order smoothness, first order zero-crossing), tightness, mean speed and variability of spiral width. Linear mixed effect adjusted models comparing these indices and cross-validation were performed. Receiver operating characteristic analysis was applied to examine discriminative validity of combined indices. Results: All indices were significantly different between PD cases and controls, except for zero-crossing. A model using all indices had high discriminative validity (sensitivity = 0.86, specificity = 0.81). Discriminative validity was maintained in patients with early PD. Conclusion: Spiral analysis accurately discriminates subjects with PD and early PD from controls supporting a role as a promising quantitative biomarker. Further assessment is needed to determine whether spiral changes are PD specific compared with other disorders and if present in pre-clinical PD. [ABSTRACT FROM AUTHOR]

Although primary dystonia is defined by its characteristic motor manifestations, non-motor signs and symptoms have increasingly been recognized in this disorder. Recent neuroimaging studies have related the motor features of primary dystonia to connectivity changes in cerebello-thalamo-cortical pathways. It is not known, however, whether the non-motor manifestations of the disorder are associated with similar circuit abnormalities. To explore this possibility, we used functional magnetic resonance imaging to study primary dystonia and healthy volunteer subjects while they performed a motion perception task in which elliptical target trajectories were visually tracked on a computer screen. Prior functional magnetic resonance imaging studies of healthy subjects performing this task have revealed selective activation of motor regions during the perception of 'natural' versus 'unnatural' motion (defined respectively as trajectories with kinematic properties that either comply with or violate the two-thirds power law of motion). Several regions with significant connectivity changes in primary dystonia were situated in proximity to normal motion perception pathways, suggesting that abnormalities of these circuits may also be present in this disorder. To determine whether activation responses to natural versus unnatural motion in primary dystonia differ from normal, we used functional magnetic resonance imaging to study 10 DYT1 dystonia and 10 healthy control subjects at rest and during the perception of 'natural' and 'unnatural' motion. Both groups exhibited significant activation changes across perceptual conditions in the cerebellum, pons, and subthalamic nucleus. The two groups differed, however, in their responses to 'natural' versus 'unnatural' motion in these regions. In healthy subjects, regional activation was greater during the perception of natural (versus unnatural) motion (P < 0.05). By contrast, in DYT1 dystonia subjects, activation was relatively greater during the perception of unnatural (versus natural) motion (P < 0.01). To explore the microstructural basis for these functional changes, the regions with significant interaction effects (i.e. those with group differences in activation across perceptual conditions) were used as seeds for tractographic analysis of diffusion tensor imaging scans acquired in the same subjects. Fibre pathways specifically connecting each of the significant functional magnetic resonance imaging clusters to the cerebellum were reconstructed. Of the various reconstructed pathways that were analysed, the ponto-cerebellar projection alone differed between groups, with reduced fibre integrity in dystonia (P < 0.001). In aggregate, the findings suggest that the normal pattern of brain activation in response to motion perception is disrupted in DYT1 dystonia. Thus, it is unlikely that the circuit changes that underlie this disorder are limited to primary sensorimotor pathways. [ABSTRACT FROM AUTHOR]

Background: Rapid eye movement sleep behavior disorder occurs with idiopathic Parkinson's disease (PD) and often precedes PD. Its frequency in LRRK2-PD and utility as a preclinical marker has not been established. Methods: One hundred forty-four idiopathic PD, 142 LRRK2 G2019S mutation PD, 117 non-manifesting carriers, 93 related noncarriers, and 40 healthy controls completed the Rapid eye movement sleep Behavior Disorder Screening Questionnaire. Results: Cut scores were met by 30.6% idiopathic PD, 19.7% LRRK2-PD, 6% nonmanifesting carriers, 20.4% related noncarriers, and 15% controls. The likelihood of abnormal scores was decreased in LRRK2-PD versus idiopathic PD (odds ratio = 0.55, P = 0.03), nonmanifesting carriers versus related noncarriers (OR = 0.25, P < 0.01), and PD of less than 3 years' duration, 1 of 19 LRRK2-PD versus 14 of 41 idiopathic PD (P < 0.05). Conclusions: A lower frequency of abnormal questionnaire scores is seen in LRRK2-PD, especially in early LRRK2-PD, and in nonmanifesting carriers. Therefore, the Rapid eye movement sleep Behavior Disorder Questionnaire is unlikely to serve as a preclinical marker for phenoconversion to PD. [ABSTRACT FROM AUTHOR]

The diagnosis of Parkinson's disease (PD) is usually not established until advanced neurodegeneration leads to clinically detectable symptoms. Previous blood PD transcriptome studies show low concordance, possibly resulting from the use of microarray technology, which has high measurement variation. The Leucine-rich repeat kinase 2 ( LRRK2) G2019S mutation predisposes to PD. Using preclinical and clinical studies, we sought to develop a novel statistically motivated transcriptomic-based approach to identify a molecular signature in the blood of Ashkenazi Jewish PD patients, including LRRK2 mutation carriers. Using a digital gene expression platform to quantify 175 messenger RNA (mRNA) markers with low coefficients of variation (CV), we first compared whole-blood transcript levels in mouse models (1) overexpressing wild-type (WT) LRRK2, (2) overexpressing G2019S LRRK2, (3) lacking LRRK2 (knockout), and (4) and in WT controls. We then studied an Ashkenazi Jewish cohort of 34 symptomatic PD patients (both WT LRRK2 and G2019S LRRK2) and 32 asymptomatic controls. The expression profiles distinguished the four mouse groups with different genetic background. In patients, we detected significant differences in blood transcript levels both between individuals differing in LRRK2 genotype and between PD patients and controls. Discriminatory PD markers included genes associated with innate and adaptive immunity and inflammatory disease. Notably, gene expression patterns in levodopa-treated PD patients were significantly closer to those of healthy controls in a dose-dependent manner. We identify whole-blood mRNA signatures correlating with LRRK2 genotype and with PD disease state. This approach may provide insight into pathogenesis and a route to early disease detection. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objective Olfactory impairment is a potential marker for impending phenoconversion to Parkinson disease ( PD) that may precede the development of disease by several years. Because of low specificity, it may be of greater predictive value in those with genetic mutations and its potential as a marker for developing LRRK2 PD should be evaluated. Methods We examined olfactory identification in 126 LRRK2 G2019S mutation carriers with PD, 125 mutation carriers not manifesting PD, 126 noncarriers with idiopathic PD, 106 noncarrier family members without PD, and 35 unrelated controls. We compared olfactory performance and performed mixture modeling to identify possible subgroups of olfactory performance in LRRK2 PD and nonmanifesting carriers. Results Adjusting for sex, age, cognitive score, site, and smoking history, LRRK2 PD had better olfactory scores compared to idiopathic PD (mean olfaction difference: −3.7, P < 0.001), and both LRRK2 PD and idiopathic PD had worse olfaction than controls (−12.8, −9.1, both P < 0.001). LRRK2 PD were less likely to be hyposmic than idiopathic PD (54.8% vs. 80.2%, P < 0.001). Nonmanifesting carriers and noncarrier family members did not differ. Mixture model analysis identified three classes in the LRRK2 PD and nonmanifesting carriers, suggesting that there are subgroups with poor olfactory identification in both LRRK2 PD and nonmanifesting carriers. Interpretation Therefore, olfactory identification deficit is less likely to be an obligate feature in LRRK2 PD than idiopathic PD, and while a relevant marker in some, a subset of carriers who eventually phenoconvert may proceed directly to PD without prior impaired olfaction. [ABSTRACT FROM AUTHOR]

ABSTRACT A founder mutation in the Thanatos-associated (THAP) domain containing, apoptosis associated protein 1 ( THAP1) gene causing primary dystonia was originally described in the Amish-Mennonites. However, there may be both genotypic and phenotypic heterogeneity of dystonia in this population that may also inform studies in other ethnic groups. Genotyping for THAP1 and for guanine nucleotide binding protein (G protein), α-activating activity polypeptide, olfactory type ( GNAL) mutations and genotype-phenotype comparisons were performed for 76 individuals of Amish-Mennonites heritage with primary dystonia. Twenty-seven individuals had mutations in THAP1-most with the founder indel mutation-but two had different THAP1 mutations, 8 had mutations in GNAL, and 1 had a de novo GAG deletion in torsin 1A ( TOR1A) (dystonia 1 [ DYT1]). In the primary analysis comparing THAP1 carriers versus all non- THAP1, non- GNAL, non- TOR1A individuals, age at onset was lower in THAP1 carriers (mean age ± standard deviation, 15.5 ± 9.2 years [range, 5-38 years] vs. 39.2 ± 17.7 years [range, 1-70 years]; P < 0.001), and THAP1 carriers were more likely to have onset of dystonia in an arm (44.4% vs. 15.0%; P = 0.02) and to have arm involvement (88.9% vs. 22.5%; P < 0.01), leg involvement (51.9% vs. 10.0%; P = 0.01), and jaw/tongue involvement (33.3% vs. 7.5%; P = 0.02) involvement at their final examination. Carriers were less likely to have dystonia restricted to a single site (11.11% in carriers vs. 65.9% in noncarriers; P < 0.01) and were less likely to have dystonia onset in cervical regions (25.9% of THAP1 carriers vs. 52.5% of noncarriers; P = 0.04). Primary dystonia in the Amish-Mennonites is genetically diverse and includes not only the THAP1 indel founder mutation but also different mutations in THAP1 and GNAL as well as the TOR1A GAG deletion. Phenotype, particularly age at onset combined with final distribution, may be highly specific for the genetic etiology. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures. Its molecular pathophysiology is poorly understood, in part owing to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1), THAP1 (DYT6) and CIZ1 (ref. 5), have been identified. Using exome sequencing in two families with PTD, we identified a new causative gene, GNAL, with a nonsense mutation encoding p.Ser293* resulting in a premature stop codon in one family and a missense mutation encoding p.Val137Met in the other. Screening of GNAL in 39 families with PTD identified 6 additional new mutations in this gene. Impaired function of several of the mutants was shown by bioluminescence resonance energy transfer (BRET) assays. [ABSTRACT FROM AUTHOR]

Summary: Background: DYT6 is a primary, early-onset torsion dystonia; however, unlike in DYT1 dystonia, the symptoms of DYT6 dystonia frequently involve the craniocervical region. Recently, two mutations in THAP1, the gene that encodes THAP (thanatos-associated protein) domain-containing apoptosis-associated protein 1 (THAP1), have been identified as a cause of DYT6 dystonia. Methods: We screened THAP1 by sequence analysis and quantitative real-time polymerase chain reaction (PCR) in 160 white patients of European ancestry who had dystonia with an early age at onset (n=64), generalised dystonia (n=35), a positive family history of dystonia (n=56), or facial or laryngeal dystonia. Another 160 patients with dystonia were screened for reported and novel variants in THAP1. 280 neurologically healthy controls were screened for the newly identified and previously reported changes in THAP1 and these and an additional 75 controls were screened for a rare non-coding mutation. Findings: We identified two mutations in THAP1 (388_389delTC and 474delA), respectively, in two (1%) German patients from the 160 patients with dystonia. Both mutation carriers had laryngeal dystonia that started in childhood and both went on to develop generalised dystonia. Thus, two of three patients with early-onset generalised dystonia with orobulbar involvement had mutations in THAP1. One of the identified patients with DYT6 dystonia had two family members with subtle motor signs who also carried the same mutation. A rare substitution in the 5′untranslated region (−236_235GA→TT) was found in 20 of 320 patients and in seven of 355 controls (p=0·0054). Interpretation: Although mutations in THAP1 might have only a minor role in patients with different, but mainly focal, forms of dystonia, they do seem to be associated with early-onset generalised dystonia with spasmodic dysphonia. This combination of symptoms might be a characteristic feature of DYT6 dystonia and could be useful in the differential diagnosis of DYT1, DYT4, DYT12, and DYT17 dystonia. In addition to the identified mutations, a rare non-coding substitution in THAP1 might increase the risk of dystonia. Funding: Deutsche Forschungsgemeinschaft; Volkswagen Foundation; Dystonia Medical Research Foundation; University of Lübeck. [Copyright &y& Elsevier]

Rapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+-ATPase α3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism. [Copyright &y& Elsevier]

Importance: Sleep disturbances in Parkinson's disease (PD) are common and often adversely affect quality of life. Light therapy has benefited sleep quality and mood outcomes in various populations but results to date with conventional light therapy boxes in PD patients have been mixed. We hypothesized that a passive lighting intervention, applied in the morning and designed to maximally affect the circadian system, would improve measures of sleep and mood in PD patients., Methods: In this single-arm, within-subjects intervention study, baseline objective sleep (actigraphy), subjective sleep quality (questionnaires), and subjective mood (questionnaires) data were collected for 1 week. Lighting was then administered to participants via table/floor lamps installed in the home or via personal light therapy glasses for 2 h in the morning, 7 days per week, over the following 4-week period. Post-intervention data for the same outcomes were collected during the final week of the intervention period., Results: Among 20 participants (12 women, 8 men; mean [SD] age 72.1 [9.5] years, disease duration 9.0 [5.2] years), objective sleep duration increased significantly by 28.5 min (p = 0.029) and objective sleep time increased significantly by 19.9 min (p = 0.026)., Conclusion: Passive and easily administered lighting interventions for improving sleep in PD patients hold promise as a treatment for mitigating symptoms and improving quality of life in PD., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Background: LRRK2 variants have been associated with immune dysregulation as well as immune-related disorders such as IBD. A possible relationship between multiple sclerosis (MS) and LRRK2 PD has also been suggested. Further, neuropathologic studies of homozygous LRRK2 G2019S carriers with Parkinson's disease (PD) are rare, and there are no systematic reports of clinical features in those cases., Methods: We investigated the co-occurrence of PD and MS in our research cohort and report on two cases of MS in LRRK2 PD as well as neuropathological findings for one., Results: MS preceded PD in 1.4% (2/138) of participants with LRRK2 G2019S variants, and in none (0/638) with idiopathic PD ( p  = 0.03). One case with MS and PD was a LRRK2 G2019S homozygous carrier, and neuropathology showed evidence of substantia nigra pars compacta degeneration and pallor without Lewy deposition, as well as multiple white matter lesions consistent with MS-related demyelination., Discussion: The increased prevalence of MS in LRRK2 PD further supports an important role for immune function for LRRK2 PD. This co-occurrence, while rare, suggests that MS may be an expression of the LRRK2 G2019S variant that includes both MS and PD, with MS predating features diagnostic of PD. The neuropathology suggests that the MS-related effects occurred independent of synuclein deposition. Importantly, and in addition, the neuropathological results not only support the MS diagnosis, but provide further evidence that Lewy body pathology may be absent even in homozygote LRRK2 carriers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wise, Ortega, Raymond, Cervera, Thorn, Leaver, Russell, Bressman, Crary and Saunders-Pullman.)

The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson's disease (PD). LRRK2, although ubiquitously expressed, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation under baseline culture conditions and following exposure to the proinflammatory factors IFNγ and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFNγ stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.

There is a paucity of genetic characterization in people with Parkinson's disease (PD) of Latino and Afro-Caribbean descent. Screening LRRK2 and GBA variants in 32 New Yorkers of Puerto Rican ethnicity with PD and in 119 non-Hispanic-non-Jewish European PD cases revealed that Puerto Rican participants were more likely to harbor the LRRK2-p.G2019S variant (15.6% vs. 4.2%, respectively). Additionally, whole exome sequencing of twelve Puerto Rican and Dominican PD participants was performed as an exploratory study., (© 2023. The Author(s).)

Primary dystonia is thought to emerge through abnormal functional relationships between basal ganglia and cerebellar motor circuits. These interactions may differ across disease subtypes and provide a novel biomarker for diagnosis and treatment. Using a network mapping algorithm based on resting-state functional MRI (rs-fMRI), a method that is readily implemented on conventional MRI scanners, we identified similar disease topographies in hereditary dystonia associated with the DYT1 or DYT6 mutations and in sporadic patients lacking these mutations. Both networks were characterized by contributions from the basal ganglia, cerebellum, thalamus, sensorimotor areas, as well as cortical association regions. Expression levels for the two networks were elevated in hereditary and sporadic dystonia, and in non-manifesting carriers of dystonia mutations. Nonetheless, the distribution of abnormal functional connections differed across groups, as did metrics of network organization and efficiency in key modules. Despite these differences, network expression correlated with dystonia motor ratings, significantly improving the accuracy of predictions based on thalamocortical tract integrity obtained with diffusion tensor MRI (DTI). Thus, in addition to providing unique information regarding the anatomy of abnormal brain circuits, rs-fMRI functional networks may provide a widely accessible method to help in the objective evaluation of new treatments for this disorder., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although men and women with the LRRK2 G2019S variant appear to be equally likely to have Parkinson's disease (PD), the sex-distribution among glucocerebrosidase (GBA) variant carriers with PD, including limited to specific variant severities of GBA, is not well understood. Further, the sex-specific genetic contribution to PD without a known genetic variant is controversial., Objectives: To better understand sex differences in genetic contribution to PD, especially sex-specific frequencies among GBA variant carriers with PD (GBA PD) and LRRK2-G2019S variant carriers with PD (LRRK2 PD)., Methods: We assess differences in the sex-specific frequency in GBA PD, including in subsets of GBA variant severity, LRRK2 PD, and idiopathic PD in an Ashkenazi Jewish cohort with PD. Further, we expand prior work evaluating differences in family history of parkinsonism., Results: Both idiopathic PD (267/420 men, 63.6%) (P &lt; 0.001) and GBA PD overall (64/107, 59.8%) (P = 0.042) were more likely to be men, whereas no difference was seen in LRRK2 PD (50/99, 50.5%) and LRRK2/GBA PD (5/10, 50%). However, among GBA PD probands, severe variant carriers were more likely to be women (15/19 women, 79.0%) (P = 0.005), whereas mild variant carriers (44/70 men, 62.9%) (P = 0.039) and risk-variant carriers (15/17 men, 88.2%) (P = 0.001) were more likely to be men., Conclusions: Our study demonstrates that the male-sex predominance present in GBA PD overall was not consistent across GBA variant severities, and a female-sex predominance was present among severe GBA variant carriers. Therefore, research and trial designs for PD should consider sex-specific differences, including across GBA variant severities. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Background and Objectives: There is clinical and phenotypic heterogeneity in LRRK2 G2019S Parkinson disease (PD), including loss of smell. Olfactory scores have defined subgroups of LRRK2 PD at baseline. We now extend this work longitudinally to better determine features associated with olfactory classes and to gain further insight into this heterogeneity., Methods: Evaluation of 162 patients with LRRK2 PD and 198 patients with idiopathic PD (IPD) from the LRRK2 Ashkenazi Jewish Consortium was performed, with follow-up available for 92 patients with LRRK2 PD and 74 patients with IPD. Olfaction (University of Pennsylvania Smell Identification Test [UPSIT]), motor function (Unified Parkinson Disease Rating Scale), and cognition (Montreal Cognitive Assessment), as well as sleep, nonmotor, and mood, were measured. Gaussian mixture models were applied on the UPSIT percentile score to determine subgroups based on olfactory performance. Linear mixed effects models, using PD duration as the time scale, assessed the relationship between UPSIT subgroup membership and motor/cognitive change., Results: Baseline olfaction was better in LRRK2 PD compared with IPD (mean UPSIT ± SD: 24.2 ± 8.8 vs 18.9 ± 7.6), with higher mean percentile scores (difference: 15.3 ± 11.6) ( p < 0.001) and less frequent hyposmia (55.6% vs 85.4%; p < 0.001). Analysis suggested 3 classes among LRRK2 PD. Age at onset in LRRK2 PD was earlier in the worst olfaction group (group 1), compared with groups 2 and 3 (54.5 ± 11.1 vs 61.7 ± 9.3) ( p = 0.012), and separately in the hyposmic group overall (55.0 ± 11.3 vs 61.7 ± 9.1) ( p < 0.001). Longitudinal motor deterioration in LRRK2 PD was also significantly faster in the worst UPSIT group than the best UPSIT group (group 3 vs group 1: B = 0.31, SE = 0.35 vs B = 0.96, SE = 0.28) (rate difference = -0.65, SE = 0.29) ( p = 0.03). However, olfactory group membership was not significantly associated with cognitive decline., Discussion: In this large LRRK2 cohort with longitudinal analysis, we extend prior work demonstrating subgroups defined by olfaction in LRRK2 G2019S PD and show that the worst olfaction group has earlier age at PD onset and more rapid motor decline. This supports a subgroup of LRRK2 PD that might show more rapid change in a clinical trial of LRRK2 -related agents and highlights the need to integrate careful phenotyping into allocation schema in clinical trials of LRRK2 -related agents., Classification of Evidence: This study provides Class II evidence that worse olfactory scores were associated with an earlier age at symptomatic onset and a faster rate of motor deterioration in patients with LRRK2 PD., (© 2022 American Academy of Neurology.)

Objective: The objective of this study was to evaluate clinical features and response to deep brain stimulation (DBS) in G2019S LRRK2-Parkinson disease (LRRK2-PD) and idiopathic PD (IPD)., Methods: The authors conducted a clinic-based cohort study of PD patients recruited from the Mount Sinai Beth Israel Genetics database of PD studies. The cohort included 87 participants with LRRK2-PD (13 who underwent DBS) and 14 DBS participants with IPD enrolled between 2009 and 2017. The baseline clinical features, including motor ratings and levodopa-equivalent daily dose (LEDD), were compared among LRRK2-PD patients with and without DBS, between LRRK2-PD with DBS and IPD with DBS, and between LRRK2-PD with subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) DBS. Longitudinal motor scores (Unified Parkinson's Disease Rating Scale-part III) and medication usage were also assessed pre- and postoperatively., Results: Compared to LRRK2-PD without DBS (n = 74), the LRRK2-PD with DBS cohort (n = 13) had a significantly younger age of onset, longer disease duration, were more likely to have dyskinesia, and were less likely to experience hand tremor at disease onset. LRRK2-PD participants were also more likely to be referred for surgery because of severe dyskinesia (11/13 [85%] vs 6/14 [43%], p = 0.04) and were less likely to be referred for medically refractory tremor (0/13 [0%] vs 6/14 [43%], p = 0.02) than were IPD patients. Among LRRK2-PD patients, both STN-DBS and GPi-DBS targets were effective, although the sample size was small for both groups. There were no revisions or adverse effects reported in the GPi-DBS group, while 2 of the LRRK2-PD participants who underwent STN-DBS required revisions and a third reported depression as a stimulation-related side effect. Medication reduction favored the STN group., Conclusions: The LRRK2-PD cohort referred for DBS had a slightly different profile, including earlier age of onset and dyskinesia. Both the STN and GPi DBS targets were effective in symptom suppression. Patients with G2019S LRRK2 PD were well-suited for DBS therapy and had favorable motor outcomes regardless of the DBS target. LRRK2-DBS patients had longer disease durations and tended to have more dyskinesia. Dyskinesia commonly served as the trigger for DBS surgical candidacy. Medication-refractory tremor was not a common indication for surgery in the LRRK2 cohort.

Mutations and variants in the glucocerebrosidase ( GBA ) gene are among the most common genetic risk factors for the development of Parkinson's disease (PD). Yet, penetrance is markedly reduced, and less is known about the burden of carrying a single mutation among those without diagnosed PD. Motor, cognitive, psychiatric, and olfactory functioning were assessed in 30 heterozygous GBA mutation carriers without PD (the majority of whom had mild GBA mutations) and 49 non-carriers without PD. Study focus was on domains affected in GBA mutation carriers with PD, as well as those previously shown to be abnormal in GBA mutation carriers without PD. GBA mutation carriers showed poorer performance on the Stroop interference measure of executive functioning when controlling for age. There were no group differences in verbal memory, Montreal Cognitive Assessment (MoCA), overall motor score, or presence of REM sleep behavior disorder or depression. Although total olfaction scores did not differ, GBA mutation carriers with hyposmia had lower global cognition scores than those without hyposmia. As anticipated by the low penetrance of GBA mutations, these findings suggest that pre-manifest non-motor or motor features of PD may not present in most GBA mutation carriers. However, there is support that there may be a subtle difference in executive functioning among some non-manifesting heterozygous GBA mutation carriers, and, combined with olfaction, this may warrant additional scrutiny as a potential biomarker for pre-manifest and pre-clinical GBA related PD., Competing Interests: SB and RS-P have received consulting fees from Denali Therapeutics Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Moran, Bressman, Ortega, Raymond, Nichols, Palmese, Elango, Swan, Shanker, Perera, Wang, Zimmerman and Saunders-Pullman.)

Importance: Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials., Objective: To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation., Design, Setting, and Participants: A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis., Main Outcomes and Measures: Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores., Results: Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08)., Conclusions and Relevance: Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.

Purpose of Review: This article highlights the clinical and diagnostic tools used to assess and classify dystonia and provides an overview of the treatment approach., Recent Findings: In the past 4 years, the definition and classification of dystonia have been revised, and new genes have been identified in patients with isolated hereditary dystonia (DYT23, DYT24, and DYT25). Expanded phenotypes were reported in patients with combined dystonia, such as those with mutations in ATP1A3. Treatment offerings have expanded as there are more neurotoxins, and deep brain stimulation has been employed successfully in diverse populations of patients with dystonia., Summary: Diagnosis of dystonia rests upon a clinical assessment that requires the examiner to understand the characteristic disease features that are elicited through a careful history and physical examination. The revised classification system uses two distinct nonoverlapping axes: clinical features and etiology. A growing understanding exists of both isolated and combined dystonia as new genes are identified and our knowledge of the phenotypic presentation of previously reported genes has expanded. Genetic testing is commercially available for some of these conditions. Treatment options for dystonia include pharmacologic therapy, chemodenervation, and surgical intervention. Deep brain stimulation benefits many patients with various types of dystonia.

Dystonia is a brain disorder characterized by abnormal involuntary movements without defining neuropathological changes. The disease is often inherited as an autosomal-dominant trait with incomplete penetrance. Individuals with dystonia, whether inherited or sporadic, exhibit striking phenotypic variability, with marked differences in the somatic distribution and severity of clinical manifestations. In the current study, we used magnetic resonance diffusion tensor imaging to identify microstructural changes associated with specific limb manifestations. Functional MRI was used to localize specific limb regions within the somatosensory cortex. Microstructural integrity was preserved when assessed in subrolandic white matter regions somatotopically related to the clinically involved limbs, but was reduced in regions linked to clinically uninvolved (asymptomatic) body areas. Clinical manifestations were greatest in subjects with relatively intact microstructure in somatotopically relevant white matter regions. Tractography revealed significant phenotype-related differences in the visualized thalamocortical tracts while corticostriatal and corticospinal pathways did not differ between groups. Cerebellothalamic microstructural abnormalities were also seen in the dystonia subjects, but these changes were associated with genotype, rather than with phenotypic variation. The findings suggest that the thalamocortical motor system is a major determinant of dystonia phenotype. This pathway may represent a novel therapeutic target for individuals with refractory limb dystonia., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: Data on the long-term cognitive outcomes of patients with PARKIN-associated Parkinson disease (PD) are unknown but may be useful when counseling these patients., Objective: Among patients with early-onset PD of long duration, we assessed cognitive and motor performances, comparing homozygotes and compound heterozygotes who carry 2 PARKIN mutations with noncarriers., Design, Setting, and Participants: Cross-sectional study of 44 participants at 17 different movement disorder centers who were in the Consortium on Risk for Early-Onset PD study with a duration of PD greater than the median duration (>14 years): 4 homozygotes and 17 compound heterozygotes (hereafter referred to as carriers) and 23 noncarriers., Main Outcomes and Measures: Unified Parkinson Disease Rating Scale Part III (UPDRS-III) and Clinical Dementia Rating scores and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS-III scores. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose., Results: Carriers had an earlier age at onset of PD (P < .001) and were younger (P = .004) at time of examination than noncarriers. They performed better than noncarriers on the Mini-Mental State Examination (P = .010) and were more likely to receive lower scores on the Clinical Dementia Rating (P = .003). In multivariate analyses, carriers performed better than noncarriers on the UPDRS-III (P = .02) and on tests of attention (P = .03), memory (P = .03), and visuospatial (P = .02) cognitive domains., Conclusions and Relevance: In cross-sectional analyses, carriers demonstrated better cognitive and motor performance than did noncarriers with long disease duration, suggesting slower disease progression. A longitudinal follow-up study is required to confirm these findings.

With increasing understanding of dystonia genetic etiologies and pathophysiology there has been renewed scrutiny and reappraisal of dystonia classification schemes and nomenclature. One important category that includes both clinical and etiologic criteria is primary dystonia. This editorialized review discusses the impact of recent findings on primary dystonia criteria and argues that it remains useful in clinical and research practice. © 2013 Movement Disorder Society., (© 2013 Movement Disorder Society.)

Rapid-onset dystonia-parkinsonism (RDP) is a rare condition with autosomal-dominant inheritance causing dystonia and parkinsonism which develop over a short period of time. It results from abnormalities in the Na(+)/K(+)-ATPase pump due to mutations in the ATP1A3 gene. This chapter reviews the clinical features, genetics, and diagnosis of this disorder., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2, PARK8) are the most commonly identified monogenic etiology of Parkinson disease (PD). Over-represented in the Ashkenazi Jewish population, these mutations are transmitted in an autosomal dominant manner with age-dependent reduced penetrance. The natural history and penetrance of these mutations in the elderly is controversial and inadequately studied. We conducted a nested cohort study in a community-based aging study (the Einstein Aging Study). Six elderly, initially nonmanifesting carriers (NMC) of the LRKK2 G2019S mutation were identified (average age 82.1 ± 7.0, range 72.7-90.8), and five had available longitudinal data. We matched five noncarrier controls to each NMC and followed them for an average of 4.7 years with annual cognitive and motor examinations. PD was identified in one NMC at age 95 and in no control subjects. The remaining carriers did not differ from controls on motor scores at baseline or follow-up. The baseline Unified Parkinson's Disease Rating Scale motor subscore (UPDRS-III) in cases was 6.2 ± 6.9 (range 1-19) and in controls was 4.5 ± 6.6 (1-30), P = 0.6; the mean difference in UPDRS-III slopes over time between cases and controls was 0.1 ± 1.3 and was not statistically significant. Our data, while limited by a small sample size, show that in LRKK2 G2019S mutation carriers, phenoconversion to PD can occur late in life. However, most NMC have motor decline which is indistinguishable from their age mates, suggesting that the larger subset of elderly NMC is not on the motor trajectory to disease., (© 2010 Movement Disorder Society.)

Several advances have been made in dystonia in both the basic science and clinical realms. Recent research has implicated dysfunctional circuitry outside of the basal ganglia, thereby broadening our understanding of the pathophysiology of dystonia. Genetic achievements include the discovery of a genetic modifier that protects against clinical expression in DYT1 and the identification of the DYT6 gene (THAP1). Several reports provided expanded descriptions of the clinical features of dystonia and its associated symptoms. Follow-up studies of deep brain stimulation, typically targeting the globus pallidus internus, have been largely positive. The success of deep brain stimulation in many cases of generalized dystonia has led to trials in other forms of dystonia, such as medically refractive cervical dystonia. This article reviews relevant recent findings in dystonia.

Background: Mutations in THAP1 were recently identified as the cause of DYT6 primary dystonia; a founder mutation was detected in Amish-Mennonite families, and a different mutation was identified in another family of European descent. To assess more broadly the role of this gene, we screened for mutations in families that included one family member who had early-onset, non-focal primary dystonia., Methods: We identified 36 non-DYT1 multiplex families in which at least one person had non-focal involvement at an age of onset that was younger than 22 years. All three coding exons of THAP1 were sequenced, and the clinical features of individuals with mutations were compared with those of individuals who were negative for mutations in THAP1. Genotype-phenotype differences were also assessed., Findings: Of 36 families, nine (25%) had members with mutations in THAP1, and most were of German, Irish, or Italian ancestry. One family had the Amish-Mennonite founder mutation, whereas the other eight families each had novel, potentially truncating or missense mutations. The clinical features of the families with mutations conformed to the previously described DYT6 phenotype; however, age at onset was extended from 38 years to 49 years. Compared with non-carriers, mutation carriers were younger at onset and their dystonia was more likely to begin in brachial, rather than cervical, muscles, become generalised, and include speech involvement. Genotype-phenotype differences were not found., Interpretation: Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families. The clinical features that are characteristic of affected individuals who have mutations in THAP1 include limb and cranial muscle involvement, and speech is often affected., Funding: Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation.

Objective: To identify research priorities to increase understanding of the pathogenesis, diagnosis, and improved treatment of spasmodic dysphonia., Study Design and Setting: A multidisciplinary working group was formed that included both scientists and clinicians from multiple disciplines (otolaryngology, neurology, speech pathology, genetics, and neuroscience) to review currently available information on spasmodic dysphonia and to identify research priorities., Results: Operational definitions for spasmodic dysphonia at different levels of certainty were recommended for diagnosis and recommendations made for a multicenter multidisciplinary validation study., Conclusions: The highest priority is to characterize the disorder and identify risk factors that may contribute to its onset. Future research should compare and contrast spasmodic dysphonia with other forms of focal dystonia. Development of animal models is recommended to explore hypotheses related to pathogenesis. Improved understanding of the pathophysiology of spasmodic dysphonia should provide the basis for developing new treatment options and exploratory clinical trials., Significance: This document should foster future research to improve the care of patients with this chronic debilitating voice and speech disorder by otolaryngology, neurology, and speech pathology.

Rapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.

Mitochondrial DNA (mtDNA) mutations can cause rare forms of dystonia, but the role of mtDNA mutations in other types of dystonia is not well understood. We now report identification by sequencing, restriction endonuclease analyses, and clonal analyses of a heteroplasmic missense A to G base pair substitution at nucleotide position 3796 (A3796G) in the gene encoding the ND1 subunit of mitochondrial complex I in a patient with adult-onset dystonia, spasticity, and core-type myopathy. The mutation converts a highly conserved threonine to an alanine. The same mutation subsequently was identified in 2 of 74 additional unrelated adult-onset dystonia patients. A muscle biopsy was obtained from 1 of these 2 subjects and this revealed abnormalities of electron transport chain (ETC) activities. The mutation was absent in 64 subjects with early onset dystonia, 82 normal controls, and 65 subjects with Parkinson's disease or multiple system atrophy. The A3796G mutation previously has been reported in 3 of 226 subjects from mitochondrial haplogroup H. Each of the 3 subjects in our study harboring the A3796G mutation was also from haplogroup H. However, a subgroup analysis of haplogroup H subjects from our study indicates that the A3796G mutation is significantly overrepresented among haplogroup H adult-onset dystonia subjects compared with haplogroup H controls (P<0.01). This difference remains significant even after excluding the index patient (P=0.04). These data suggest that, among haplogroup H subjects, the presence of the A3796G mutation increases the risk of developing adult-onset dystonia.

Myoclonus-dystonia is a movement disorder associated with mutations in the epsilon-sarcoglycan gene (SGCE) in most families and in the DRD2 and DYT1 genes in two single families. In both of the latter families, we also found a mutation of SGCE. The molecular mechanisms through which the detected mutations may contribute to myoclonus-dystonia remain to be determined.